Submission Details

SPEF2 was first described as a primary ciliary dyskinesia (PCD)-causing gene in 2020 (Cindrić et al., PMID: 31545650). Variants in SPEF2 had also been previously identified in individuals affected with multiple morphologic abnormalities of the flagella (PMID: 31151990) and asserted as a monogenic cause of spermatogenic failure 43 (MIM#: 618751). Probands diagnosed with spermatogenic failure displayed male infertility and reduced sperm motility, often without reported details of respiratory examinations, but sometimes in the confirmed absence of respiratory features (PMID: 31048344). Those diagnosed with primary ciliary dyskinesia exhibited respiratory symptoms including chronic rhinitis or sinusitis, bronchiectasis, productive/wet cough, and otitis media, in addition to infertility and reduced sperm motility (PMID: 31942643). Per the recommendations of the ClinGen Lumping & Splitting Working Group, the GCEP found consistencies between the mode of inheritance (autosomal recessive) and molecular mechanism (biallelic SPEF2 loss-of-function) between patients diagnosed with either infertility or primary ciliary dyskinesia, while their overlapping phenotypes formed a single spectrum that included both infertility and respiratory features. As. a result, the GCEP recommended lumping of all SPEF2-related cases into a single gene curation under the broader disease entity primary ciliary dyskinesia (MONDO:0016575).

This curation includes eleven variants (six frameshift, three nonsense, one missense, and one splice site) that have been reported in eight probands in five publications (PMIDs: 36615117, 31545650, 36873931, 31942643, 31048344). Overall, the mechanism of pathogenicity appears to be biallelic loss-of-function.

This gene-disease relationship is also supported by multiple forms of experimental evidence ranging from expression to animal models (PMIDs: 31545650 and 21715716). PCD probands with HYDIN variants show SPEF2 expression / localization defects by immunofluorescence (PMID: 31545650). In addition, the mouse "big giant head" (bgh) model with homozygous Spef2 disruption is characterized not only by hydrocephalus but also male infertility, abnormal ciliary motility, sinusitis and reduced respiratory ciliary beating frequency, which recapitulated the phenotypes found in human probands (PMID: 21715716).

In conclusion, SPEF2 is definitively associated with primary ciliary dyskinesia. This classification has been clearly demonstrated and confirmed through both experimental and genetic evidence and has been upheld over time without the emergence of contradictory evidence. This classification was approved by the Motile Ciliopathy GCEP on January 9th, 2025 (SOP Version 11).